Gene expression alterations in immune system pathways following exposure to immunosuppressive chemicals

Exposure to environmental agents can affect a number of adverse immunological outcomes, including changes in the incidence of infectious disease. Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that can induce similar pathophysiological end points in the thymus; however, the mechanism of toxicity is different for each compound. We examined differential gene expression in the spleen and thymus following chemical exposure and correlated these changes with alterations in functional immune end points and our knowledge of the known mechanisms of action. RNA from the spleen and thymus has been analyzed using Illumina Sentrix arrays and BeadStudio software. Preliminary data suggest that DES induced the greatest number of gene changes in the spleen, while DEX induced the most changes in the thymus. In both spleen and thymus, genomic analysis revealed gene expression changes that were common to multiple chemicals and that may be associated with xenobiotic-induced immune system perturbations, including alterations in genes associated with apoptosis, antigen processing and presentation, and response to biotic stimulus. This was particularly evident in the thymus, where there were many similarities in the expression profiles, as well as gene alterations unique to a single compound. In contrast, expression profiles in spleen were more distinct. The category of genes most profoundly affected by all four chemicals was response to biotic stimulus: there were both clusters of genes modulated by multiple chemicals and genes altered by a single chemical. The distinct gene profiles may specifically relate to cellular targets and mechanism of action.